Researchers map the neurons and connections involved in the Gate Control Theory of pain.


Sensing pain is extremely unpleasant and sometimes hard to bear, and pain can even become chronic. The perception of pain varies a lot depending on the context in which it is experienced.  Fifty years-ago Patrick Wall and Ronald Melzack formulated the so-called ‘Gate Control Theory’ of pain. The two researchers proposed that inhibitory nerve cells in the spinal cord determine whether a pain impulse coming from the periphery, such as the foot, is relayed to the brain or not.

Now, a team from the University of Zurich have identifed which inhibitory neurons in the spinal cord are responsible for this control function. As the opensource study published in the journal Neuron shows, the control cells are located in the spinal dorsal horn and use the amino acid glycine as an inhibitory messenger.

With the aid of genetically modified viruses the researchers specifically interfered with the function of these neurons in mice. They discovered that disabling the glycine-releasing neurons leads to an increased sensitivity to pain and signs of spontaneous pain. Moreover, the team developed viruses that enabled these specific pain-control cells to be activated pharmacologically.

The team state that the mice treated with these viruses were less sensitive to painful stimuli than their untreated counterparts and activating these nerve cells alleviated chronic pain. The findings also showed that the neurons don’t just control pain, but also various forms of itch.

One key aspect of the Gate Control Theory is that various influences can modulate the pain-controlling neurons’ activity. Based on a person’s experience from everyday life, for instance, they know that gently rubbing or holding an injured extremity can alleviate pain in this area. According to the theory, non-painful contact with the skin is supposed to activate the inhibitory cells. In the current study the researchers were able to verify this hypothesis and confirm that the inhibitory, glycine-releasing neurons are innervated by such touch-sensitive skin nerves.

The team were able to demonstrate that neurons on the superficial layers of the spinal cord, where the relay of the pain signals takes place, are primarily inhibited by glycine signals.  The researchers surmise that these three findings identify for the first time the neurons and connections that underlie the Gate Control Theory of pain.

The researchers state that the targeted stimulation or inhibition of particular types of neurons in humans is still a long way off and might only be possible in a few decades’ time  adding that another way may well reach the target sooner, namely via the receptors that are activated by the inhibitory neurons.

As these receptors are located on the neurons that relay pain signals to the brain, their specific pharmacological activation should also block pain with the group already achieving promising initial results in this field.

Source:  University of Zurich and ETH Zurich

 

Specific Loss of Inhibitory Interneurons after AAV.flex.DTA Injection into the Dorsal Horn of GlyT2::Cre+ Mice.  Sagittal sections of aspinalcord after injection of AAV.flex.DTA illustrateamarkedreduction in the numberof Pax2+ cells onthe ipsilateral side but not on the contralateral side.  Targeted Ablation, Silencing, and Activation Establish Glycinergic Dorsal Horn Neurons as Key Components of a Spinal Gate for Pain and Itch.   Zeilhofer et al 2015.

Specific Loss of Inhibitory Interneurons after AAV.flex.DTA Injection into the Dorsal Horn of GlyT2::Cre+ Mice. Sagittal sections of aspinalcord after injection of AAV.flex.DTA illustrateamarkedreduction in the numberof Pax2+ cells onthe ipsilateral side but not on the contralateral side. Targeted Ablation, Silencing, and Activation Establish Glycinergic Dorsal Horn Neurons as Key Components of a Spinal Gate for Pain and Itch. Zeilhofer et al 2015.

 

 

 

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